Viruses pose a constant threat to human health in substantial part because of the evolution of their entry proteins. This evolution can enable viruses to infect new species (including humans), and to evade antibody-based immunity. We will integrate approaches from genomics, computation, and virology to develop a general platform to prospectively characterize how mutations to a virus's entry protein affect its ability to infect cells and resist neutralization by antibodies. This platform can be used to study the entry proteins of an extremely wide range of viruses. We will use it to characterize the effects of all amino-acid mutations to the entry proteins from four important emerging viruses: Ebola virus, MERS coronavirus, Lassa virus, and Nipah virus. We will comprehensively identify mutations that affect the ability of these viruses to infect cells from relevant host species, and use the results to inform algorithms that assess a virus's host adaptation from sequence. We will also develop algorithms that leverage the platform to quantify how all mutations to a viral entry protein affect its susceptibility to antibody-based immunity. Overall, this work develops a powerful and general method to prospectively characterize the implications of viral mutations.